PROJECT ABSTRACT Approximately 6000 children in the USA die from in-hospital cardiac arrests (IHCAs) each year, and 21-33% are sepsis-associated. Although >40% of children with IHCAs survive to hospital discharge, children with sepsis-associated cardiac arrests are 35% less likely to survive to discharge. Children with sepsis-associated IHCAs often have pulmonary hypertension. Yet nearly all animal investigations of cardiac arrest and CPR have focused on ventricular fibrillation or asphyxia cardiac arrests rather than cardiac arrests associated with shock, pulmonary hypertension, and systemic inflammation, common key components of sepsis-associated cardiac arrests. New biologically plausible therapeutic approaches addressing the special CPR circumstance of pediatric sepsis-associated cardiac arrests are needed to improve outcomes from this under-studied and highly lethal problem. The goal of this grant proposal is to establish that the novel addition of a pulmonary vasodilator, inhaled nitric oxide (iNO), during cardiopulmonary resuscitation (CPR) can improve coronary perfusion pressures and improve survival rates from intractable cardiac arrests associated with lipopolysaccharide (LPS)-induced shock and pulmonary hypertension in the context of systemic inflammation. Our preliminary CPR data in 30 kg (3 month old) swine and 10 kg (1 month old) piglets demonstrate that outcomes are uniformly fatal from LPS-induced shock-associated cardiac arrests despite aggressive state-of- the-art resuscitation techniques because of LPS-induced acute pulmonary hypertension. As expected, the pulmonary hypertension was much worse in the more immature 1 month old piglets. In this proposal, we will evaluate the novel addition of pulmonary vasodilator therapy with iNO during CPR for LPS-induced shock- associated cardiac arrests in 30 kg (3 mo) swine and more immature 10 kg (1 mo) piglets. Our overall hypothesis is that the addition of a potent pulmonary vasodilator during CPR will improve short-term survival. Aim 1: Determine whether the blinded addition of iNO during CPR can improve short-term survival compared to resuscitation with no iNO during CPR in a 30 kg (3 mo) swine model of LPS-induced shock-associated pediatric cardiac arrest. Aim 2: Determine whether the blinded addition of iNO during CPR can improve short-term survival compared to resuscitation with no iNO during CPR in a 10 kg (1 mo) piglet model of LPS-induced shock-associated pediatric cardiac arrest. This novel highly translatable, biologically plausible and readily available intervention may provide an effective alternative for a developmentally broad group of children who have poor outcomes with our current therapeutic approaches, and has the potential to save thousands of lives worldwide each year.